Genetic pathways to delay the onset of aging have been elucidated in many organisms. Despite the vast differences in maximal lifespan across species some of the mechanisms that control lifespan are evolutionary conserved. The aim of this proposal is to identify and characterize novel mechanisms of lifespan extension that display evolutionary conservation. The long-term goal of this project is acertain the genetic mechanisms in place that regulate the aging process in mammals. The first specific aim examines four genes identified in a RNAi screen for increased lifespan. These four genes aside from increasing adult lifespan postdevelopmentally also misregulate the germline/soma cell type specificity. This phenotype although previously undescribed is shared with known regulators of lifespan and may contribute to both the increased lifespan and enhanced resistance to stress. Specific aim 2 utilizes a classical genetic screen to identify new regulators in three pathways that influence lifespan in C. elegans. A pilot study has identified 22 genetic mutants that regulate the worms response to three distinct pathways which when reduced in function increase mean adult lifespan. Despite the diversity in these cellular pathways a subset of these mutants regulate all three mechanisms, and may represent master regulators of lifespan. Mapping and characterization of these genetic mutants will identify novel regulators of C. elegans longevity. Finally, 64 genes were previously identified in a post-developmental RNAi screen for increased lifespan in C. elegans. More than 90% of these genes are conserved from yeast to man. Specific aim 3 will characterize the orthologs of these genes in fly and mouse, which may reveal conserved mechanisms of lifespan extension. We will test the ability of the mammalian orthologs to rescue the loss of function phenotype in the worm. Using GFP reporters in the worm along with bioinformatic and RT-PCR expression analysis of the mouse orthologs we will compare the tissues where these novel lifespan regulators function. Using these criteria we will pick our best candidates for conserved longevity regulators and test post-developmental knockdown in the fly and targeted temporal/tissue specific disruptions in the mouse. RELEVANCE: Results from this study are important for public health as with age comes an increased incidence of disease and this study will provide insight into essential cellular pathways that regulate lifespan as well as answer many fundamental questions in cell biology.